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Redox proteins, including metalloproteins, form a large portion of the protein kingdom. Metalloproteins themselves form ~ 30% of a genome. These contain metal ions either as a single atom or as part of a cluster and play a variety of life sustaining roles in the bacterial, plant and animal kingdoms. Many enzymes exploit the oxidation states of metals to perform redox cycling. Fundamental biological processes in which metalloproteins participate include electron storage and transfer, dioxygen binding, storage and activation, and substrate transport, catalysis and activation. In many metalloenzymes such as cytochrome c oxidase (essential for mammalian life through respiratory requirements), nitrogenases and nitrite reductases (essential in view of their central position in the nitrogen cycle), hydrogenases (producers of molecular hydrogen - a candidate for a future alternative energy source), catalysis involves the controlled delivery of electrons and protons to the active site where substrate is utilised. The proposal build on close collaboration between the applicants and the RIKEN group (Japan) where they collectively have made major contributions in the field of denitrification and have provided significant advances in our understanding of complex processes that are involved in biological mechanisms of metalloenzymes. Our combined approaches have allowed us to build detailed three dimensional structural movies of catalysis in the crystalline state, thereby providing detailed insight into enzyme reaction chemistry. Our recent determination of structures for the membrane proteins, nitric oxide reducatses (Tosha & Shiro, RIKEN) together with the atomic resolution structure of the tethered cytochrome-Cu1-Cu2 nitrite reductase (Antonyuk, Eady & Hasnain, UoL) puts us in a very strong position to establish an integrated structural-mechanistic biology programme. This programme is aimed at understanding complex mechanisms of redox control, regulation and communication in globally important biological systems. General principles emerging from these studies will underpin our understanding of the control of redox processes in biology and protection against toxic chemical intermediates like nitric oxide. New methods and approaches developed in this programme (e.g. development of laboratory-based size-exclusion chromatography-small angle X-ray scattering with dynamic light scattering (SEC-SAXS-DLS) for studying protein complexes) will have broad relevance to our capabilities for studying protein complexes. These new capabilities and the scientific outcome will have significant impact on structural-mechanistic biology and keep the UK at the forefront of global effort in this important field.

Information technology (IT) has penetrated all aspects of life in modern society. At the heart of IT are miniature devices that can process and store information in one or another form. Currently, the information is processed mainly within semiconductor based data architectures based on tiny "transistors". In contrast, long-term data storage is dominated by magnetic hard disk drives, within which the information is stored as direction of tiny "magnetic needles" the two opposite orientations of which represent "0" and "1" values in binary logics. However, the semiconductor industry is predicted to reach the limit of miniaturisation within the coming decade, while the energy consumption becomes increasingly important both for environmental concerns and to align with use in portable battery fed devices. In this project, we aim to demonstrate a key component of a novel device for information technology, which has the potential to lead to combined data processing and storage on the same chip. This device will be based upon 'magnonics', in which wave-like perturbations of magnetisation ('spin waves') travel through and interact in patterned magnetic tracks ('waveguides') to perform operations. We propose to construct a spin wave source such that the wave properties of many such sources are linked; technically, this is known as 'coherence'. Our proposed spin wave source consists of a magnetic nanowire antenna placed across the waveguides. Microwave radiation will create magnetic oscillations in the antennae, which in turn will induce the spin waves in the nearby waveguides. Spin waves are proposed as logic signal carriers, thereby assisting their seamless integration with existing and future magnetic data storage technologies. This integration of signal processing and storage within a single architecture promises reduced energy consumption and fast device operation. In addition, we will exploit how the spin waves interact with the magnetic configuration of the various components. The materials and geometry of the antennae and waveguides causes the magnetisation to prefer to lie along their length. However, opposite magnetisations can be engineered to meet within, say, the waveguide to create a transition region called a 'magnetic domain wall'. By selectively configuring the orientation of the magnetic waveguide and antennae, including incorporation of magnetic domain walls, we will be able to program the magnonic device functionalities. The magnetic materials we propose to use don't require power to retain their magnetisation (non-volatility), meaning our devices will store the configuration when powered off and, therefore, will be instantaneously bootable upon switch on. The multiple stable configurations of the magnetic components and associated multiple functionalities will also provide an opportunity for creating more complex devices that could replace several semiconductor transistors in conventional electronics. Apart from consumer electronics, the devices will be advantageous for use in aerospace, space and sub-marine technologies in which their non-volatility and resistance to radiation will allow vital weight and cost savings to be made. The collaborative research programme will be conducted jointly by the Department of Materials Science and Engineering at the University of Sheffield and the College of Engineering, Mathematics and Physical Sciences at the University of Exeter. The Sheffield team will contribute to the project their internationally leading expertise in nanotechnology and manipulation of magnetic domain walls, while the Exeter team will contribute their world leading expertise in dynamical characterization and theoretical modelling of magnonic devices. By joining their forces together, the two teams will ensure that UK will remain at the forefront at the magnetic logic technology, in particular opening the new interdisciplinary field of domain wall magnonics.

Uranium, the heaviest naturally occurring element, is the main component of nuclear waste. In air, and in the environment, it forms dioxide salts called uranyl compounds, which are all based around a doubly charged, linear O=U=O group. These compounds are very soluble and are problematic environmental groundwater contaminants. The U=O bonds are also extraordinarily chemically robust and show little propensity to participate in the myriad of reactions that are characteristic of transition metal dioxide analogues which have chemical and catalytic uses in both biological and industrial environments. Due to relativistic effects, thorium, another component of nuclear waste, and a potential nuclear fuel of interest due to the lower proliferation risk, also does not have straightforward, predictable chemistry, and is a remarkably soft +4 metal ion. The behaviour of its molecular oxides is poorly understood, although tantalising glimpses of what might be possible come from gas phase studies that suggest oxo structures completely unlike the other actinyl ions. Uranium's man-made and highly radioactive neighbour neptunium forms linear O=Np=O dications like uranium, but due to the extra f-electron, shows much more oxygen atom reactivity. In nuclear waste, cation-cation complexes form with U, Np, and Pu when the oxo groups bind to another metal dioxo cation, making the behaviour of the mixtures harder to predict. However, by adding an electron to the uranyl ion, we and others have shown in recent years that the singly reduced uranyl can provide a more oxo-reactive, better model for the heavier actinyls. Since the route for precipitating uranium from groundwater involves an initial one-electron reduction to an aqueous-unstable intermediate, these stable U(V) uranyl complexes are potentially important models for understanding how uranium is precipitated. Our work to uncover actinyl ion reactivity similar to that seen in transition metal oxo chemistry has focused on using a rigid organic ligand framework to expose one of the oxygen atoms. We have most recently reported a smaller, more constrained macrocycle that can bind one or two uranium or thorium cations, so far in the lower oxidation states. This also allowed us to look at covalency in the metal-ligand and metal-metal interactions. We will use the control afforded by these two rigid ligands to make a series of actinide oxo complexes with new geometries. Some, including more chemically esoteric projects, are initially anticipated to be purely of academic interest, and an important part of researcher training. Some of the reactions will have more relevance to environmental and waste-related molecular processes, including proton, electron, and oxo group rearrangement, transfer, and abstraction. Results concerning the reactivity of these new complexes will help us better understand the more complex metal oxo systems found in nuclear wastes and the environment. We will look at hydrocarbon C-H bond cleavage by the most reactive actinide oxo complexes, working on pure hydrocarbon substrates, but recognising the relevance to the destruction of organic pollutants induced by photolysis of uranyl. Working at the EU Joint research centre for transuranic research at the ITU (Karlsruhe), we will also study the neptunium analogues of these complexes. The molecularity of these systems will also make the magnetism of mono- and bimetallic complexes easier to understand and model than solid-state compounds. The experts at the ITU will be able to identify whether the two metals communicate through a central oxo atom or even through ligand pi-systems. We will also provide samples to collaborators at the INE (institute of nuclear waste disposal), Karlsruhe and Los Alamos National Labs, USA, to obtain XAS data that allow the study of the valence orbitals, metal-metal distances/interactions (from the EXAFS) and covalency (from the ligand edge XAS).

The proposed UK Consortium on Turbulent Reacting Flows will perform high-fidelity computational simulations (i.e. Reynolds Averaged Navier-Stokes simulations (RANS), Large Eddy Simulation (LES) and Direct Numerical Simulations (DNS)) by utilising national High Performance Computing (HPC) resources to address the challenges related to energy through the fundamental physical understanding and modelling of turbulent reacting flows. Engineering applications range from the formulation of reliable fire-safety measures to the design of energy-efficient and environmentally-friendly internal combustion engines and gas turbines. The consortium will serve as a platform to collaborate and share HPC expertise within the research community and to help UK computational reacting flow research to remain internationally competitive. The proposed research of the consortium is divided into a number of broad work packages, which will be continued throughout the duration of the consortium and which will be reinforced by other Research Council and industrial grants secured by the consortium members. The consortium will also support both externally funded (e.g. EU and industrial) and internal (e.g. university PhD) projects, which do not have dedicated HPC support of their own. The consortium will not only have huge intellectual impact in terms of fundamental physical understanding and modelling of turbulent reacting flows, but will also have considerable long-term societal impact in terms of energy efficiency and environmental friendliness. Moreover, the cutting edge computational tools developed by the consortium will aid UK based manufacturers (e.g. Rolls Royce and Siemens) to design safe, reliable, energy-efficient and environmentally-friendly combustion devices to exploit the expanding world-wide energy market and boost the UK economy. Last but not least, the proposed collaborative research lays great importance on the development of highly-skilled man-power in the form of Research Associates (RAs) and PhD students of the consortium members, who in turn are expected to contribute positively to the UK economy and UK reacting flow research for many years to come.

Ion imaging, first demonstrated just 25 years ago, is already having a major impact on the way we explore molecular change (the very essence of chemistry) in many gas phase systems. The technique has features in common with mass spectrometry (MS). Both start by removing an electron from the target species, generating ions, i.e. charged molecules or fragments, which are then 'sorted' by their mass. In traditional MS, the species of interest is characterised by its spectrum of ion yield versus mass. Electron removal in most ion imaging experiments is induced by a short pulse of laser light; the resulting ions are then accelerated towards a time and position sensitive detector. Heavier ions travel more slowly, so one can image ions of just one particular mass by ensuring that the detector is only 'on' at the appropriate time. The spatial pattern of ion impacts that builds up on the detector when the experiment is repeated many times is visually intuitive, and provides quantitative energetic information about the reaction(s) that yields the monitored product. However, the read out time of current ion imaging detectors is too slow to allow imaging of ions with different mass formed in the same laser shot, and many species are not readily amenable to ionisation in current ion imaging schemes. Imaging all products from a given reaction is therefore time consuming (at best) and, at worst, impossible. We seek to solve both these limitations. Two of the team have already demonstrated new, much faster, time and position sensitive sensors capable of imaging multiple masses in a single shot experiment. This multimass imaging capability will be developed further and rolled-out for use and refinement across the team. We also propose new multiphoton ionization schemes as well as 'universal' ion formation methods based on use of shorter laser wavelengths or short duration pulses of energy selected electrons. The following over-arching scientific ambitions will proceed in parallel, and exploit the foregoing advances in ion imaging technology at the earliest possible opportunity: (i) We will use the latest ion imaging methods to explore molecular change in the gas phase, focusing on key families of (photo)chemical reactions: addition, dissociation, cyclisation and ring opening reactions of organic molecules, and metal-ligand and metal-cluster interactions. These choices reflect the importance of such reactions in synthesis, catalysis, etc., their amenability to complementary high level theory, and our ability to explore the same reactions in solution (using a new ultrafast pump-probe laser spectroscopy facility). Determining the extent to which the mechanisms and energetics of reactions established through exquisitely detailed gas phase studies can inform our understanding of reactivity in the condensed phase is a current 'hot' issue in chemical science, which the team is ideally placed to address. (ii) We will develop and exploit new multi-dimensional analytical methods with combined mass, structural and spatial resolution. Mass spectra usually show many peaks attributable to fragment ions, but the paths by which these are formed are often unclear. Imaging MS is proposed as a novel means of unravelling different routes to forming a given fragment ion; distinguishing and characterising such pathways can offer new insights into, for example, peptide structure. Yet more ambitious, we propose to combine multimass and spatial map imaging with existing laser desorption/ionisation methods to enable spatially resolved compositional analysis of surfaces and of samples on surfaces. Such a capability will offer new opportunities in diverse activities like tissue imaging (e.g. detection of metal ions within tissue specimens of relevance to understanding the failure of some metal-on-metal hip implants), forensic analysis (e.g. 'chemical' imaging of fingerprints, inks, dyes, pollens, etc) and parallel mass spectrometric sampling (e.g. of blood samples).

Many diseases are caused by the faulty function of various different cell types. In order to understand what can go wrong and how it can be fixed, it is important to know as well as possible how a cell works. The fundamental problem is to understand how the 20- to 30,000 genes in a mammalian cell regulate each other. Depending on how 'active' a gene is, RNA is produced at a certain rate and will eventually be translated into proteins. Protein products of some genes can bind to DNA and regulate activity of other genes (sometimes their own), thus forming an extremely complex gene regulatory network. The interactions within this network are constantly fluctuating strongly. It is thus particularly puzzling how a cell manages to keep control in spite of this background noise. This high complexity posed an insurmountable obstacle until very recently. New developments in experimental technologies are currently revolutionizing research in biology and provide a means to address this problem. These novel technologies are largely based on remarkable advances in sequencing DNA and allow probing in parallel many factors important for gene regulation. A tremendous amount of data is produced by such experiments. This requires extensive computational analyses but makes it possible for the first time to study such a complicated regulatory network and its background noise. A better understanding of this network will provide fascinating new insights into the general molecular mechanisms that control cell function and will open up clinical perspectives for the cases where this function is defective.

Organ failure and tissue loss are challenging health issues due to widespread aging population, injury, the lack of organs for transplantation and limitations of conventional artificial implants. There is a fast growing need in surgery to replace and repair soft tissues such as blood vessels, stent, trachea, skin, or even entire organs, such as bladder, kidney, heart, facial organs etc. The high demand for new artificial implants for long-term repair and substantially improved clinical outcome still remains .Our well-publicised successes in using tissue-engineering to replace hollow organs in cases of compassionate need have shown the world that an engineering approach to hollow organ replacement is feasible, as well as serving to highlight those areas where more work is required to provide bespoke manufactured tissue scaffolds for routine clinical use Being able to replicate a functional part of one's body as an exact match and therefore to be able to replace it 'as good as before' is familiar in science fiction. Most implants will share limitations that are associated with either the materials used or the traditional way in which they have been made. With the advancement of additive manufacturing technology, 3D printing, biomaterials and cell production, printing an artificial organs is becoming a science and engineering fact and understandably can save lives and enhance quality of life through surgical transplantation of such printed organs produced on-demand, specifically for the individual of interest. The project seeks to addresses the unmet need in traditional implants by exploiting our proprietary polymer nanocomposites developed at UCL and advanced digital additive manufacturing with surgical practice. we aim to develop a 3D advanced digital bio-printing system for polymer nanocomposites in order to manufacture a new-generation of synthetic soft organs 'on-demand' and bespoke to the patient's particular needs. Our extensive preclinical and on-going preclinical study on the nanocomposite-based organs will ensure the construct is able to induce angiogenesis and to perform function of an epithelium. Here we take these experiences in the compassionate case, and take trachea as an exemplar to develop a manufacturing method of producing bespoke tubular organs for transplantation with nanocomposite material. This proposal will allow us to develop; a) a customer made 3D bioprinter with multi-printing heads and an environmental chamber which can print 'live' soft organs/scaffolds with seeded cells to meet the individual patients needs; b) a series of polymer nanocomposites suitable for 3D printingorgan constructs/host scaffolds; c) a formulations of bio-inks for printing cells, proteins and biomolecules. d) a printed artificial tracheal constructs using their radiographic images with optimised biochemical, biophysical and mechanical properties. e) Establishment of in-vivo feasibility data through observation of restoration of respiratory function and normal tissue integration of pig models which will be surgically transplanted

Chemistry is a dynamic subject that is at the centre of many different scientific advances. Organic chemistry is concerned with the reactivity of carbon in all its different forms and can be viewed as the chemistry taking place within living things. Chemists are constantly looking for new ways of designing and building molecules (synthetic chemistry is molecular architecture) and this proposal describes a short and powerful new way of making valuable molecules using a new type of catalyst. The molecules at the heart of the proposal are compounds containing a carbon-oxygen double bond (a carbonyl group) which have special properties and are the building blocks of many known pharmaceutical agents. The novel chemistry proposed here will provide a new, efficient and powerful way of making carbonyl compounds using catalysis to control all aspects of the structures of the products formed: this will be of great benefit to both academia and industry who will be able to make interesting molecules (some that were otherwise inaccessible) in new ways. Plans have also been made to screen the compounds that we make for a wide range of biological activity. Given all of the above, it is imperative that we have novel, efficient and powerful methods for making new carbonyl containing compounds so that we can study and use them. In addition, the development and application of new catalysts and catalytic systems is also important because catalysis makes chemical reactions run faster, and become cleaner with less waste: this is clearly a good thing for industry and also for the environment. The Fellowship aspect of this proposal is designed to allow the principal investigator the time to study and develop a new research direction. Plans have been made to interact and collaborate with other academics who can provide specialist knowlege and also with two project partners (one a multi-national pharmaceutical company and the other a leading academic in the United States of America) so that industrial problems and mechanistic details can be identified and addressed at all stages of the project. Three post-doctoral assistants will be employed to carry out the exprimental work, and the project will provide a thorough and comprehensive training in science and the attendant areas of communication/ presentation and creativity. This will equip them very well for the job market afterwards.

We seek support from EPSRC strategic funds to secure the appointment of a high profile academic from overseas to establish a new Sustainable Processing of Chiral Molecular Materials research group at the University of Nottingham. The group will be a key part of the University's strategy and plans to establish a Centre of Excellence for Sustainable Chemistry in collaboration with the UK based pharmaceutical company GSK. The centre will build upon the University's existing strengths in Green Chemistry, multi-disciplinary links between Chemistry and Engineering, and strong links with industry to generate a critical mass of world-leading research capacity in the emerging discipline of Sustainable Chemistry. The new research group will be housed in a unique Carbon Neutral Laboratory (CNL) and will help address key global challenges within Society and Industry including lowering carbon footprint, optimising energy usage, reducing waste and conserving precious resources such as water and metals. This work will contribute towards several of EPSRC's challenge themes. The group will be led by Professor David Amabalino (currently at CSIC-Barcelona) and will explore novel sustainable processing routes to chiral molecular materials for use in energy and medicinal applications in a multi- and inter-disciplinary collaboration across Schools in the Faculty of Science, Engineering and Medicine and Health Sciences at Nottingham, and with leading academic collaborators. Funding is requested for 50% of the salary costs of the new appointee alongside key resources to establish and pump prime the research programme. This includes two 5 year postdoctoral fellowships together with consumables, equipment and associated costs.

In 2011, NERC began a scoping exercise to develop a research programme based around deep Earth controls on the habitable planet. The result of this exercise was for NERC to commit substantial funding to support a programme entitled "Volatiles, Geodynamics and Solid Earth Controls on the Habitable Planet". This proposal is a direct response to that call. It is widely and generally accepted that volatiles - in particular water - strongly affect the properties that control the flow of rocks and minerals (their rheological properties). Indeed, experiments on low-pressure minerals such as quartz and olivine show that even small amounts of water can weaken a mineral - allowing it to flow faster - by as much as several orders of magnitude. This effect is known as hydrolytic weakening, and has been used to explain a wide range of fundamental Earth questions - including the origin of plate tectonics and why Earth and Venus are different. The effect of water and volatiles on the properties of mantle rocks and minerals is a central component of this NERC research programme. Indeed it forms the basis for one of the three main questions posed by the UK academic community, and supported by a number of international experts during the scoping process. The question is "What are the feedbacks between volatile fluxes and mantle convection through time?" Intuitively, one expects feedbacks between volatiles and mantle convection. For instance, one might envisage a scenario whereby the more water is subducted into the lower mantle, the more the mantle should weaken, allowing faster convection, which in turn results in even more water passing into the lower mantle, and so on. Of course this is a simplification since faster convection cools the mantle, slowing convection, and also increases the amount of volatiles removed from the mantle at mid-ocean ridges. Nevertheless, one can imagine many important feedbacks, some of which have been examined via simple models. In particular these models indicate a feedback between volatiles and convection that controls the distribution of water between the oceans and the mantle, and the amount topography created by the vertical movement of the mantle (known as dynamic topography). The scientists involved in the scoping exercise recognized this as a major scientific question, and one having potentially far reaching consequences for the Earth's surface and habitability. However, as is discussed in detail in the proposal, our understanding of how mantle rocks deform as a function of water content is remarkably limited, and in fact the effect of water on the majority of mantle minerals has never been measured. The effect of water on the flow properties of most mantle minerals is simply inferred from experiments on low-pressure minerals (olivine, pyroxenes and quartz). As argued in the proposal, one cannot simply extrapolate between different minerals and rocks because different minerals may react quite differently to water. Moreover, current research is now calling into question even the experimental results on olivine, making the issue even more pressing. We propose, therefore, a comprehensive campaign to quantify the effect of water on the rheological properties of all the major mantle minerals and rocks using a combination of new experiments and multi-physics simulation. In conjunction with 3D mantle convection models, this information will allow us to understand how the feedback between volatiles and mantle convection impacts on problems of Earth habitability, such as how ocean volumes and large-scale dynamic topography vary over time. This research thus addresses the aims and ambitions of the research programme head on, and indeed, is required for the success of the entire programme.